Lyu Wenting, Zhang Yuqing, Zhang Zhen, Lu Hao
College of Pharmacy, Heze University, Heze 274000, China.
Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne 3010, Australia.
Antibiotics (Basel). 2025 Feb 25;14(3):231. doi: 10.3390/antibiotics14030231.
() is a major pathogen causing severe infectious diseases, with an escalating issue of antimicrobial resistance that threatens the efficacy of existing antibiotics. Given the challenges in developing traditional antibiotics, drug repurposing strategies offer a novel approach to address the resistance crisis. This study aims to evaluate the antibacterial and anti-biofilm activities of the approved non-antibiotic anticancer drug carmofur against multidrug-resistant , and investigate the mechanism of action, and assess therapeutic potential in vivo. Antimicrobial tests revealed that carmofur exhibited strong antibacterial activity against multidrug-resistant strains, with minimum inhibitory concentrations (MICs) ranging from 0.25 to 1 µg/mL. In the biofilm detection experiments, carmofur not only inhibited the formation of biofilms, but also effectively removed biofilms under high concentration conditions. Mechanistic studies showed that carmofur disrupted bacterial membrane permeability and decreased intracellular ATP levels. Molecular docking and dynamics simulation assays indicated that carmofur could stably bind to thymidylate synthase through hydrogen bonding and hydrophobic interactions, thereby exerting antibacterial effects. Meanwhile, carmofur was able to repress the expression of the gene at the mRNA level. In a mouse infection model, the carmofur treatment group showed a reduction of approximately two log levels in bacterial load in lung tissue and blood, a significant decrease in the levels of inflammatory cytokines TNF-α and IL-6, and an improvement in survival rate to 60%. In summary, carmofur demonstrated significant antibacterial and anti-biofilm activities against multidrug-resistant and showed good anti-infective effects in vivo, suggesting its potential clinical application as a therapeutic agent against drug-resistant bacteria.
（）是引起严重传染病的主要病原体，其抗菌耐药性问题不断升级，威胁着现有抗生素的疗效。鉴于传统抗生素研发面临的挑战，药物重新定位策略为应对耐药危机提供了一种新方法。本研究旨在评估已获批的非抗生素抗癌药物卡莫氟对多重耐药菌的抗菌和抗生物膜活性，研究其作用机制，并评估其体内治疗潜力。抗菌测试表明，卡莫氟对多重耐药菌株表现出较强的抗菌活性，最低抑菌浓度（MIC）范围为0.25至1μg/mL。在生物膜检测实验中，卡莫氟不仅抑制生物膜的形成，而且在高浓度条件下能有效去除生物膜。机制研究表明，卡莫氟破坏细菌膜通透性并降低细胞内ATP水平。分子对接和动力学模拟分析表明，卡莫氟可通过氢键和疏水相互作用与胸苷酸合成酶稳定结合，从而发挥抗菌作用。同时，卡莫氟能够在mRNA水平抑制基因的表达。在小鼠感染模型中，卡莫氟治疗组的肺组织和血液中的细菌载量降低了约两个对数水平，炎症细胞因子TNF-α和IL-6水平显著降低，存活率提高到60%。总之，卡莫氟对多重耐药菌表现出显著的抗菌和抗生物膜活性，并在体内显示出良好的抗感染效果，表明其作为抗耐药菌治疗剂的潜在临床应用价值。
